A number of pediatric liver diseases, such as alpha1-anti-trypsin deficiency, cystic fibrosis, Wilson disease and mitochondrial fatty acid oxidation defects are characterized by abnormalities in protein folding and/or cellular trafficking of trace metals and organic anions may also cause the cholestatic liver diseases associated with overload of copper, iron and bile acids. This program project will examine the hypothesis that the development and severity of liver injury in these diseases is determined in part by the fate of abnormally folded proteins, trace metals or ions as directed by the quality control systems of the cell (chaperons, degradation pathways) and by the host response to their accumulation in specific subcellular compartments (e.g. heat shock, unfolded protein and autophagic responses). In project 1, D. Perlmutter will study alpha1-AT deficiency by using cell lines with inducible expression of mutant alpha1- ATZ to examine its fate in the endoplasmic reticulum (ER) and by establishing transgenic mice with liver-specific inducible expression of alpha1-ATZ to examine the in vivo response to ER retention. In project 2, G. Bu and A.L. Schwartz will examine fundamental mechanisms for quality control within the ER, including studies of a novel ER chaperone system and of the fate of LDL receptor mutants that are retained in the ER. In project 3, A. Strauss will examine the role of mitochondrial trifunctional protein deficiency in the pathogenesis of acute fatty liver of pregnancy and Reye's syndrome. In project 4, J. Gitlin will examine the role of the copper chaperone HAH1 in Wilson disease and other pediatric hepatic copper storage disorders. The core facilities include: A) Morphology Core with confocal microscopy and a unique immune electron microscopy serve at the Dept. Cell Biology, University Utrecht, Netherlands; B) Genetically Altered Mouse Core affiliated with the Child Health Research Center at Washington University; and C) Administrative Core. This program will thus provide new information about the pathogenesis of pediatric liver disease through a collaborative multi- disciplinary strategy.